This invention relates to non-toxic hydrophilic polyurethane elastomers which are intended to come into contact with tissue and/or fluids of a living body. Particularly, it relates to polyurethane elastomers which are hydrogels, i.e. materials which exhibit the ability to swell in water and retain greater than about 20 weight percent of water within their structures while being water-insoluble. Still more particularly, the polyurethane elastomers can be cured non-exothermically and after curing contain less than about 0.5% extractables. More particularly, it relates to the use of such materials as matrices from which medications, particularly water-soluble medications, can be released predictably over a prolonged period of time through the skin or mucosa of a patient. Still more particularly, it relates to elastomers prepared from polyurethane oligomers, which are fluid at room temperature, in combination with a photoinitiator which contains at least one chemical group which will enable the absorber to become chemically bound into, and thus not extractable from, the cured elastomer after exposure to actinic radiation. Still more particularly, this invention relates to incorporating a medication into the polyurethane oligomer photoinitiator composition and polymerizing the fluid composition by exposing it to ultraviolet light at about room temperature to yield a controlled delivery system for hydrophilic, hydrophobic, lipophilic, lipophobic, as well as insoluble materials which is non-toxic to humans and which also avoids exposure of the medication to elevated temperatures.
In the preparation of any material intended for use in contact with or inside a living body, it is self-evident that the materials must be non-toxic. Thus if a toxic ingredient has been used in preparing such materials, it must be either totally removed or rendered non-toxic before actual use. In the manufacture of acrylic contact lenses, for instance, toxic initiators which are necessary for the polymerization reaction to occur can be and are removed before use, generally by extended and expensive, i.e. for 24 hours or more, leaching. In such systems avoidance of leaching procedures or similar operations to overcome the toxicity problem would clearly be desirable.
Such systems can not be used to deliver water-soluble medications by incorporating a medication therein, since any type of leaching procedure would of necessity remove the desired water-soluble medication at the same time it removed the undesired toxic component. As a result, presently available controlled delivery systems have been limited to the delivery of water-insoluble or substantially water-insoluble medications. The lack of a suitable hydrophilic delivery system which is simultaneously non-toxic and does not use heat in its formation has precluded the use of controlled delivery systems with water-soluble medications.
Current commercially available hydrogels generally fall into six general categories: poly(hydroxyalkyl methacrylates); polyacrylamides, polymethacrylamides and derivatives; poly(N-vinyl-pyrrolidone); anionic and cationic hydrogels; polyelectrolyte complexes; and polyvinyl alcohols. These materials suffer from a common problem: a lack of sufficient mechanical strength for many uses. This is especially a problem as the equilibrium water content within the three dimensional networks of covalently or ionically crosslinked hydrophilic polymers reaches 10% or higher due to swelling from interaction with aqueous solutions. As the water contents increase, the hydrogels become weaker and are easily torn. This low strength makes them unsuitable for applications in which they would be subjected to mechanical stress or abrasion.
Moreover, when dry several of the prior hydrogels are exceptionally brittle, necessitating their continual storage in an aqueous environment. In the case of contact lenses, this is advantageous since it renders the lenses ready for use. But the water storage also precludes the incorporation of medications into contact lenses since the medication would dissolve into the water during storage. While the brittleness problem could be solved by adding a suitable plasticizer, this would likely render the materials toxic due to the extractability of the plasticizer.
There is thus a need for an elastomeric hydrophilic polymer which is curable non-exothermically and which contains less than about 0.5 weight % of total extractables as prepared, i.e. without having to perform a leaching-type procedure. There is also a need for a material having the following combination of properties: elastomeric to be able to conform to any desired shape, sufficiently hydrophilic to be capable of absorbing water and water-soluble materials, non-toxic to man or animal, capable of releasing the water and water-soluble materials, liquid or at least flowable at close to room temperature before polymerization, and polymerizable to a solid form without heat.
U.S. Pat. No. 4,614,787 discloses a drug dispensing wound dressing based upon an actinic radiation curable polyurethane polymer matrix which is a reaction product of isophorone diisocyanate, a macroglycol which is preferably polypropylene glycol, and a chain terminator. The patent teaches: "Other high molecular weight glycols, such as polyethylene glycol (PEG) may be employed, but PEG is a solid at room temperature and a feasible rate of reaction would require heating." It uses ultraviolet photosensitizers, such as benzophenones, which are extractable from the final cured compositions, to effect curing. It also must be noted that wound dressings are intended for use in a physiologically unique environment in regard to the general delivery of drugs through intact skin since plasma exudate inherent from a wound will absorb any lipophilic compounds and carry them into a body extremely rapidly. However, the drug dispensing wound dressings disclosed would be inoperative in the absence of the exudate from an open wound, and, due to the presence of the extremely toxic benzophenone-type photosensitizers used in preparing the wound dressings, they would not be considered safe for use by various government regulatory agencies, e.g. the U.S. Food and Drug Administration. Also, the wound dressings contain several percent toxic extractables from the photosensitizers.
Similarly, U.S. Pat. No. 4,483,759 discloses an actinic radiation cured polyurethane acrylic copolymer containing toxic benzophenone-type photosensitizers. As such, the copolymers contain several percent toxic extractables and are not considered safe for human use.
U.S. Pat. No. 4,300,820 discloses a water absorptive composition capable of absorbing more than 45% of its weight of water and comprised of a vinyl lactam polymer or copolymer in combination with a water-insoluble copolymer. The blend of the two polymers is intended to control the equilibrium water content since the greater the amount of the insoluble polymer, the lower the water content.
U.S. Pat. No. 3,996,934 discloses a medical bandage having a reservoir of a drug within a wall member formed from a drug release rate controlling material which is permeable to the passage of the drug. The patent operates on different principles than does the present invention and does not suggest the use of ultraviolet light curing systems.
U.S. Pat. No. 3,975,350 discloses hydrophilic or hydrogel carrier systems such as coatings, body implants and other articles. While the articles which are produced contain essentially no extractables, they are NCO-terminated resins which are cured by the use of extended heat, i.e. 100.degree. C. for about 48 hours, conditions which would be harmful to many drugs. No room temperature polymerizing systems are possible with the polymer systems disclosed.
Accordingly, there is a need for an elastomeric hydrophilic polymer which is both non-toxic and polymerizable in the absence of heat. It is an object of the present invention to provide such a material.
It is a further object of the invention to produce an elastomeric hydrogel containing substantially no extractables and which will cure upon exposure to ultraviolet radiation for a period of less than about two minutes.
It is a still further object of the present invention to provide a material which is strong yet flexible and which can be conformed to curved, flat as well as angular shaped bodies without cracking or other similar damage occurring.
These and still further objects and features of the present invention will be understood by those skilled in the art from a reading of the following detailed description of the invention.